Heterocyclic amides



United States Patent HETEROCYCLIC AMIDES Margaret H. Sherlock,Bloomfield, and Nathan Sperher,

North Caldwell, N.J.,assignors to Schering Corporation, Bloomfield,N.J., a corporation of New Jersey No Drawing. Application April 29, 1957Serial No. 655,539

9 Claims. I (Cl. 260-443) wherein X is a member of the group consistingof hydrogen, chlorine, fluorine, bromine, lower alkanoyl, andtrifluoromethyl, and R is a lower alkyl group.

We have found that our new compounds possess significant physiologicalproperties useful in the treatment of bronchospasm and Parkinsonsdisease. Furthermore, the compounds of this invention show remarkableselectivity in blocking pilocarpine-induced bronchospasm withoutcausing-undesirable side effects such as mydriasis andxerostemia.Moreover, our compounds, in doses sufficient to block the invitrospasmodic eflfects of acetylcholine on the tracheal chain and perfusedlung, are equally active in blocking the spasmodic effects of histamine.Thus, our compounds appear to possess a combination of anticholinergicand antihistaminic activities, which are unique in their specificity fortreatment of bronchospasm.

The ability to block pilocarpine-induced bronchospasm appears to be aproperty of both the isonipecotoylphenothiazines of our invention andtheir L l-isomers, the nipecotoylphenothiazines. We have found, however,that our compounds are significantly more potent and have a morefavorabletherapeutic ratio than their isomers. For example, viaintravenous administration in dogs, we have found that10-(N-methylisonipecotoyl)-phenothiazine is 33 times'as potent asatropine and 11 times as potent as its 3-isomer,IO-(N-methylnipecotoyl)-phenothiazine in relieving bronchospasm.Furthermore, the isonipecotoyl derivative has greater specificity ofaction with minimal side effects. In view of the advantageoustherapeutic ratio, the isonipecotoyl derivatives are distinct from, andpreferred to, their position isomers.

The present treatment of Parkinsonism has been limited by the appearanceof undesirable side eifects produced by the medicament employed. Theunique specificity of the compounds of our invention in overcoming theeffects panied by a similar specificity of cholinergic blockade withinthe central nervous system without untoward side efiects. Theseadvantageous properties make our compounds more effective than agentscurrently employed in Parkinsonism and provide for favorable control ofsymptons without concomitant side effects.

The compounds of our invention are readily prepared via a conventionalamide synthesis. Reacting a phenothiazine or its 2-X substitutionproducts, wherein X is as above defined, with an N-lower alkylisonipecotoyl halide yields the amides of our invention. We prefer touse an acid salt of an isonipecotoylchloride such asN-methylisonipecotoylchloride hydrochloride and effect the reaction inan inert solvent such as benzene, toluene, xylene and the like. Tohasten the reaction we prefer to heat the mixture, generally at reflux.

The acid salts are usually prepared from the free base and a non-toxicacid preferably in an inert solvent such as ether, benzene, ethylacetate and the like, whereby the salt precipitates in a relatively purestate. Examples of non-toxic salts which may be prepared in this mannerare the hydrochloride, phosphate, maleate, citrate, tartrate, salicylateand the like.

The following examples are intended merely to illustrate the inventionand are not to be construed as limiting the 'scope thereof:

EXAMPLE 1 l0-(N-methylisanipecotoyl)-phenothiazine Phenothiazine (40 g.)is added portionwise to a suspension of N-methylisonipecotoylchloridehydrochloride (from 36 g. of N-methylisonipecotic acid hydrochloride) in800 ml. anhydrous benzene. The reaction mixture is stirred and refluxedfor 12 hours, then one liter of water is added. The aqueous layer isseparated and the henzene layer extracted several times with dilutehydrochloric acid. The acid extracts combined with the original aqueouslayer are basified with dilute sodium hydroxide solution, and a gummymaterial separates which slowly crystallizes. Several recrystallizationsfrom benzene-petroleum ether yields 10-(N-methylisonipecotoyl)-phenothiazine as a yellow solid, M.P. 179l80 C.

The hydrochloride is prepared from the free base with ethanolic hydrogenchloride. The salt is obtained as the monohydrate, and melts at 241-242C., after several recrystallizations from ethanol-ether.

EXAMPLE 2 10- (N-methylisonipecotoyl) -2-chlorophen0thiazz'ne crudeproduct is filtered from the benzene solution andrecrystallized fromethanol to yield the hydrochloride salt of 10-(N-methylisonipecotoyl) 2chlorophenothiazine, M.P. 2635-2645 C.

When the hydrochloride salt so obtained is dissolved in hot water andthe resulting solution made basic with of aoetyl-choline in bronchialsmooth muscle is accomsodium hydroxide solution, the free base,IO-(N-methylisonipecotoyl)-2-chlorophenothiazine is precipitated,filtered, and recrystallized from ethanol-water, M.P.

EXAMPLE 3 10- (N-methylisonipecotoyl)-2-br0mophen0thiazine scribed inExample 2. The hydrochloric acid salt of 10-(N-methylisonipecotoyl)-2-bromophen0thiazine which is formed,crystallizes from methanol as colorless crystals. When the hydrochloridesalt so obtained is further treated as in Example 2, the free base isisolated as a light tan solid which is crystallized from ethanol-water.

EXAMPLE 4 10-(N-isopropylisonipecotoyl) -phenothiazine The requisiteintermediate, methyl N-isopropylisonipecotate, B.P. 127-l30 C./3 mm. Hg,is prepared by the alkylation of methyl isonipecotate with potassiumcarbonate and isopropyl iodide in benzene.

A solution of 17.5 g. of methyl N-isopropylisonipecotate and 100 ml. ofconcentrated hydrochloric acid is heated on a steam bath for 16 hours,concentrated to dryness, then refluxed for two hours with 50 ml. ofthionyl chloride. After the excess thionyl chloride is removed in vacuo,the residual solid is suspended in 400 ml. of anhydrous benzene, and 20g. of phenothiazine is added portionwise. The reaction mixture isstirred and refluxed for 12 hours. One liter of water is then added, theaqueous layer separated, and the basic layer extracted several timeswith dilute hydrochloric acid. The acid extracts combined with theoriginal aqueous layer are made basic with dilute sodim hydroxidesolution and are then extracted with ether. The ether solution is cooledto --30 C. in an acetone Dry Ice bath and the green solid whichprecipitates is filtered. Extraction of the solid in a Soxhlet extractorwith hexane yields 10-(N- isopropylisonipecotoyl)-phenothiazine as ayellow crystalline solid.

This crystalline amide is converted to the maleatesalt in ethyl acetatewith an equimolar amount of maleic acid in ethyl acetate.

EXAMPLE 5 1 0- (N -methylisonipec0toyl -2-acetylphen0thiazineZ-acetylphenothiazine g.) is reacted with a suspension ofN-methylisonipecotoylchloride hydrochloride (from 10.7 g. ofN-methylisonipecotic acid hydrochloride) in 200 ml. of anhydrousbenzene, in the manner described in Example 2, to yield the hydrochloricacid salt of 10 (N-methylisonipecotoyl) 2 acetylphenothiazine which iscrystallized from methanol. When the hydrochloride salt M.P. 225226 C.(monohydrate) so obtained is further treated as in Example 2, the ,freebase is isolated as a light tan solid which is crystallized fromethanol-water.

EXAMPLE 6 10-(N-methylisonipecotoyl) -2-trifluoromethylphenothi- .azineTo a stirred solution of 2-trifiuoromethylphenothiazine (21 g.) in 200ml. of dry benzene, there is added crude N-methylisonipecotoylchloridehydrochloride (from 18 g. of N-methylisonipecotic acid hydrochloride).The reaction miXture is stirred and refluxed for 18 hours, then 500 ml.of water is added. The aqueous layer is sepa rated and made basic withsodium hydroxide. The oil which separates is extracted with benzene, andthese extracts, in turn, are concentrated in vacuo .to an oily residue.This residue is dissolved in 200 ml. of hexane treated with charcoal,filtered and cooled. The product of our invention,.10-(N-methylisonipecotoyl)e2etrifiuoromethylphenothiazine, precipitatesas a tan solid (3.12 g.) M.P. 136-137.-5 .C.

The hydrochloride salt of the above compound is prepared by adding anethanolsolution of hydrogen chloride to a solutoin of the free base inmethyl ethyl ketone until the solution is faintly acidic. With theaddition of dry ether, the hydrochloride precipitates as a colorlesssolid which melts at 235-236 C. after recrystallization from methylethyl ketone.

The compounds .ofpur invention can be incorporated into various oralpharmaceutical preparations such as tablets, capsules, elixirs, syrups,nasal sprays, suppositories, and the like, by mixing the same alone, orin conjunction with other active ingredients with various proportions ofpharmaceutical carriers suitable for the preparation being made. Activeingredients which may be used with the compounds of our invention are:aminophylline, prednisone, ephedrine sulfate, potassium iodide, codeinsulfate or phosphate, phenobarbital, perphenazine, calcium phosphate,chlorpheniramine maleate, and the like. The recommended optimum dose.range for oral administration of the claimed compounds, is from 0.5 to2 mg. t.i.d.

The compounds of our invention can also be administered intravenously,preferably in the form of aqueous solutions of their non-toxic aminesalts (such as the hydrochloride), in the presence of preservatives suchas methyl paraben, propyl paraben, and the like. Other activeingredients such as those used in the oral preparations may also be usedin these parenteral compositions. From 0.1 to 0.4 mg. of thephenothiazine compound per parental dose is the optimum rangerecommended.

The proportions of active ingredients in our compositions can be variedover a substantial range, subject to the practical limitation that asufficient proportion of active ingredient be present to provide asuitable dosage. Obviously, the practice of administering several unitdosage forms at about the same time can be followed. The dosage of thesecompounds may be varied, depending on the requirements of the patient.The following formulations are intended as illustrative only, and arenot to be construed as limiting the scope of the invention.

EXAMPLE 7 Table 10- N-methylisonipecotoyl) -phenothiazine hydrochloride1.00 Lactose 48.05 Starch 20.60 Starch paste Gs Magnesium stearate 0.35

The 10-(N-methylisonipecotoyl) -phenothiazine hydrochloride is mixedwith the lactose and the starch. A 10 percent starch paste is preparedand the-mixed powders granulated therewith. This wet granulation ispassed through a No. 12 screen and then dried at 50 C. for twelve hours,or until the moisture content is less than 0.5 percent. The dry granulesare passed through aNo. 16 screen, incorporated with the remainder ofthe starch and-magnesium 'stearate, and then pressed into tablets.

The 1'0-(N-methylisonipecotoyl) phenothiazine hydrochlorideaminophylline, and calcium phosphate 'are' made int'o'tablets'bytheprocedure described in Example'7.

.EXAMPLE 9 .Hard, gelatin capsule10-(N-methylisonipecotoyl)-phenothiazine hydrochloride 1.00 Prednisone,-5.0.0 Lactose l 432.00 Magnesium :stearate M,.... 2.00

The 10 (N methylisonipecotoyl) PbmQFh aZinehydrochloride and prednisoneare mixed thoroughly with the lactose. Magnesium stearateisthen addedand mixed until the composition is uniform; No. 1 hard shell capsulesare then filled with this uniform mixture.

EXAMPLE 10 Soft gela tirt capsule Mg.10-(N-methylisonipecotoyl)#phenothiazine hydrochloride 1.00 Ephedrinesulfate 25.00 Lactose 10.00 Beeswax 2.00 Corn oil 5 172.00

One milligram of -(N-methylisonipecotoyl)-phenothiazinehydrochlorideiand 25 milligramsaof ephedrine sulfate are mixed with thelactose, then passed throughla No. 180 meshscreen. --This mixture isadded to the 90m small opening size; The beeswax, whichhad been meltedat 60 C., is poured into this milled suspensionjwith constant stirring.Stirring is continued until there is a homogeneous suspension which isfilled into so'ft gelatin capsules. Seal capsules.

EXAMPLE 11 1A;

Elixir chloride Aminophylline, U.S.P. XV' Amaranth, U.S.P. XV.. Syrup,U.S.P. XV Glycerin, U.S.P. XV Orangeoil, U.S.P. XV Alcohol, U.S.P. XVPurified water, U.S.P. XV., q.s. 1:01.

EXAMPLE 12 Syrup 10- (N-methylisonipecotoyl)-pheno Quantity/l. 10 (Nmethylisonipecotoyl)-phenothiazine hydrochloride gm 0.2 Potassiumiodide, U.S.P. XV -..gm 13.0 Compound sarsaparilla syrup, N.F. X, 1.0 1.

The 10-(N-methylisonipecotoyl)-phenothiazine hydrochloride and potassiumiodide are dissolved in a quantity .of compound sarsaparilla syrupsufficient to make the total volume measure one liter. The solution isfiltered, if necessary, until clear.

EXAMPLE 13 I Suppository Gm. 10 (N methylisonipecotoyl) -phenothiazinehydrochloride 0.1 Aminophylline, U.S.P. XV 30.0 Theobroma oil, U.S.P.XV-A sufiicient quantity to make 100 suppositories.

The ingredients are mixed intimately and prepared according to theprocess of cold compression to form 100 rectal suppositories, each ofwhich weighs approximately 2 gm.

oil and put through a rotor and atator type mill setiat a 6.;=;EXAMPLE:14- 1- a Nasaldrop and/or spray r r Quantity/l.1Q-(N-methylisonipecotoyl) -phenothiazine hydro 1 chloride g 1.0Chlorpheniramine maleate, U.S.P. XV gm.. 3.0 Sorbitol solution, N.F. Xgm 70.0 Benzalkonium chloride solution, 12.8% ml 1.95

Purified water, q.s. 1.01.

The 10-(N-methylisonipecotoyl)-phenothiazine hydrochloride andchlorpheniramine maleate are dissolved in a suitable quantity of water.The sorbitol and benzalkonium chloride solutions are added, thensufiicient purified water to make the total volume of one liter. Thesolution is filtered until clear.

v ,EXAMPLE 15 Parenteral solution Gm./ liter 10 (N methylisonipecotoyl)-phenothiazine hydrochloride 1 0.10 Methyl Paraben 1.80 Propl Paraben0.20

Water for injection, q.s. ad. 1.00 liter.

The ingredients are dissolved in the water for injection, filtered,filled into ampules or vials, and sterilized by autoclaviug.

EXAMPLE 16 Parenteral solution 10 (N-methylisonipecotoyl)-phenothiazinehydrochloride gm lliter..- 0.20 Phenobarbital gm./liter 15.00

I Propylene glycol 900 Methyl Paraben gm./liter 1.8 Propyl Parabengm./liter 0.2

Water for injection, q.s. ad. 1.00 liter.

The 10-(N-methylisonipecotoyl)-phenothiazine hydrochloride is dissolvedin about 50 ml. of water for injection. The other ingredients aredissolved in the propylene glycol. The solutions are mixed, bringing thevolume to one liter with water'for injection, filtered, filled intoampules or'vialsi and sterilized by autocl'avingj l EXAMPLE 17Parenteral solution Gm./liter 10 (N methylisonipecotoyl)-phenothiazinehydrochloride 0.20 1 (2 hydroxyethyl) 4[3 (2 chloro10-phenothiazinyl)-propyl] piperazine 0.10 Sodium biphosphate 20.0Sodium phosphate 1.5 Methyl Paraben 1.8 Propyl Paraben 0.2

Water for injection, q.s. ad. 1.00 liter.

The ingredients are dissolved in the water for injection, filtered,filled into ampules or vials, and sterilized by autoclaving.

We claim:

1. Compounds having the formula:

It JWGI alkyl wherein X is a member of the group consisting of hy- 7 8drogen, lower alkanoyl;ttifiuoromethyl, and a halogen sf'l'heuo'thiazines having the formula: atom having anatomioweight between 30and 80, and the non-toxic acid addition salts thereof. 4 l I s .1

2. Phenothiazines having the formula:

N E=o If, lower'alkyl N my] wherein X is lower alkanoyl. v 6.10-(N-methylisonipecotoyl)-phenothiazine. 3. Phenothlazmes having theformula: 7;; trifiuommethylr .10 (N-methylisonipecotoyl)- 'sphenothiazine.

8. 2 acetyl- 10 (N-methylisonipecotoyl) pheno- 7 thiazineo 'Q 9. '2chloro 1O (N-methylisonipecotoyl) pheno- =0 thiazine.

References Cited in the file of this patent UNITED STATES PATENTS N2,587,660 Smith Mar. 4, 1952 2,591,679 Cusic Apr. 8, 1952 alkyl2,690,441 Burtner Sept. 28, 1954 4. Phenothiazines'having the formula:2,712914 Suter June 28, 1955 2,753,352 Bernstein July 3, 1956..2,768,202 Goldberg Oct. 23, 1956 m FOREIGN PATENTS 829,297 GermanyJan. 24, 1952 662,903 Great Britain Dec. 12, 1951 129,371 Sweden Dec.12, 1950 40 OTHER REFERENCES Dahlborn: Acta Pharmcol et toxicoL, vol. 9,pp. 168- r I I 1 n 178 (1953).

alkyl Dahlbom: Acta Chem. Scand., vol. 5, pp. 102-114 wherein Hal. is ahalogen having anatomic weighttbe- (1951), tween 30 and 80. Massie:Chem. Reviews, vol. 54, pp. 798-833 (1954).

1. COMPOUNDS HAVING THE FORMULA: WHEREIN X IS A MEMBER OF THE GROUPCONSISTING OF HYDROGEN, LOWER ALKANOYL, TRIFLUOROMETHYL, AND A HALOGENATOM HAVING AN ATOMIC WEIGHT BETWEEN 30 AND 80, AND THE NON-TOXIC ACIDADDITION SALTS THEREOF.